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Ewers et al. use data from ADNI to understand relationships between β amyloid (Aβ) and longitudinal change in brain structure and function (measured with MRI and FDG-PET, respectively), as well as longitudinal cognitive decline. The results provide an in-depth view of complex relationships, revealing robust effects in MCI—higher Aβ was associated with volume loss across many regions of interest (ROIs) and decline in metabolism, as well as longitudinal change in cognition—and weak to null relationships within normals (a relationship was only seen between Aβ and volume loss in a few ROIs), despite comparable levels of Aβ in Aβ-positive MCI and normal subjects.

These analyses reiterate an important question that resonates in studies unveiling elevated Aβ in cognitively normal elderly controls: How is it possible that these subjects with high pathological burden remain normal? Although this question is not directly tested by Ewers et al., the weaker relationships between amyloid and brain measures in Aβ-positive normals compared to Aβ-positive MCI subjects provide evidence that certain individuals can have high levels of this pathology without concurrent downstream consequences (such as atrophy and hypometabolism).

There are a number of potential explanations for this discrepancy in Aβ-positive normals. An obvious and simple explanation may be that they have been accumulating Aβ for a shorter amount of time (they are earlier on the trajectory towards AD, before downstream events have occurred), or perhaps have been depositing Aβ at a slower rate (a rate that may not be neurotoxic and/or allows sufficient time for compensatory responses to take place). Another potential mechanism could be via heightened resistance to Aβ pathology in these individuals (perhaps through genetics, neuronal plasticity, high brain reserve, etc.). Finally, it is possible that Aβ-positive normals lack pathologies that exacerbate effects of Aβ (such as neurofibrillary tangle pathology, which may have an etiology independent of Aβ, or may be downstream of Aβ and has not yet emerged in these normals. See Desikan et al., 2011, for an analysis relevant to this claim.) These proposed mechanisms are not necessarily exclusive, and may interact together to enable certain normal individuals to "cope" with Aβ.

Future studies that address these potential mechanisms will clarify the relevance of this pathology in cognitively normal elderly individuals and during early AD development.